Fingolimod‐associated Balo's concentric sclerosis in multiple sclerosis: A case report

Key Clinical Message A report of Balo's concentric sclerosis developed alongside with fingolimod use in a patient with previously diagnosed multiple sclerosis.


| INTRODUCTION
Multiple sclerosis (MS) is a chronic autoimmune disease that primarily affects women and young adults and characterized by demyelination of the central nervous system. 1 Current management approaches are concentrated on symptom relief, acute attack treatment, and lowering biological activity through disease-modifying therapies (DMT). 2 The first oral DMT licensed for the treatment of MS is fingolimod. 3Atypical demyelinating disorders exhibiting tumor-like features present significant diagnostic and therapeutic challenges for neurologists.Tumefactive demyelinating lesions (TDLs) are rare tumor-like lesions in the central nervous system presenting diverse symptoms that predominantly affect motor, cognitive, sensory, cerebellar, and brainstem functions. 4Balo's concentric sclerosis (BCS) emerges as an uncommon variant of TDLs, distinguished radiologically by a "tree trunk" or "onion bulb" appearance on magnetic resonance imaging (MRI), characterized by alternating bands of myelin preservation and loss around them. 5,6Despite TDLs being observed in MS patients on fingolimod, 7 documentation on Balo-like lesions remains limited.Herein, we present a young female MS patient treated with fingolimod who was admitted to our clinic with hemiparesis and a Balolike lesion in her MRI.

| CASE HISTORY/EXAMINATION
A 37-year-old female with a 9-year history of relapsingremitting MS (RRMS) and 3-year fingolimod treatment presented to Sina Hospital's emergency department in Tehran, Iran, exhibiting acute right-sided hemiparesis persisting for 5 days.The patient had no complaints of fever, headache, diplopia, imbalance, or aphasia.She was alert and oriented at admission, and her vital signs were stable.Her pupils were normal in size and had a normal reaction to light.Eye movements were normal in all directions, with no observed ptosis, lid lag, or nystagmus.A physical examination of muscles revealed normal tone in upper and lower limbs on both sides and a medical research council score of 3/5 for proximal and distal muscles of the right upper and lower limbs and 4/5 for proximal and distal muscles of the left upper limb and 5/5 for proximal and distal muscles of the left lower limb.Deep tendon reflexes were assessed using a reflex hammer on the biceps, triceps, brachioradialis, patellar, and Achilles tendon.The reflex responses were normal on the left side and increased on the right side.

| METHODS
A brain MRI was requested, revealing closed ring and target lesions in the left parietal lobe, prompting consideration of infectious etiologies (Figure 1).Subsequent lumbar puncture yielded normal cerebrospinal fluid (CSF) biochemistry results (WBC: 0, RBC: 2, glucose: 69 mg/dL, and protein: 16 mg/dL).Additional studies on CSF, including tuberculosis, brucella, cryptococcus, wright, coombs wright, venereal disease research laboratory, and angiotensin-converting enzyme, were negative.Moreover, CSF cytologic assessments did not reveal any signs of malignant cells.Patient had anemia and lymphopnia on complete blood count assessment (Hb: 9.2 gr/dL, WBC: 4.4 × 10 3 /μL, lymphocyte: 12.7%, and neutrophil: 84.3%).Further laboratory examinations, including renal and liver function tests, erythrocyte sedimentation rate, C-reactive protein, blood sugar, arterial blood gas, toxoplasmosis, JC virus, urine analysis, urine culture, stool exam, stool culture, and serum electrolytes, did not yield any pathologic findings.Viral markers, including hepatitis B core antibody, hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody, were nonreactive.Additional abdominopelvic CT scan was performed to assess any signs of malignancy or metastases, which did not reveal any pathologic findings.

| CONCLUSION AND RESULTS
With infectious causes ruled out, fingolimod-induced BCS emerged as the leading diagnosis.As the BCS could be caused by fingolimod, the drug was discontinued, and 1 g/day of IV methylprednisolone was administered for 5 days, resulting in improved limb strength by the fifth day of corticosteroid therapy.Subsequently, rituximab was initiated 15 days after fingolimod cessation.We followed the patient monthly and she exhibited improvement in symptoms, with the absence of any new focal neurological deficits noted during 8-month follow-up assessments.

| DISCUSSION
In this case report, we describe a young patient diagnosed with MS who had been under treatment with fingolimod for 3 years.The patient presented to our clinic exhibiting symptoms of hemiparesis, and upon examination, we detected a Balo-like lesion in her MRI scan without any symptomatic indications of infection.
Fingolimod is an unselective modulator of the sphingosine-1-phosphate (S1P) receptor and is commonly used by clinicians to manage relapsing forms of MS (RRMS). 2 It is generally well-tolerated, while side effects might include mild abnormalities in standard laboratory evaluations, 8,9 heart block, bradycardia, macular edema, as well as infections including disseminated varicella-zoster virus and cryptococcal infections. 10Notably, patients with MS receiving fingolimod treatment may develop TDLs even after several years. 7DLs are lesions greater than 2 cm on T2-weighted brain MRI that can be similar to tumors. 11Although TDLs can be observed in various diseases such as autoimmunemediated encephalitis, acute disseminated encephalomyelitis (ADEM), myelinoclastic diffuse sclerosis (Schilder's disease), neuromyelitis optica spectrum disorder (NMOSD), and BCS, 5 MS represents the most prevalent association. 12 Several hypotheses exist regarding the underlying mechanisms of TDL formation induced by fingolimod in MS patients.It has been suggested that immune cell redistribution occurs in susceptible MS patients, with effector CD8+ T cells, a subset of cytotoxic cells, being particularly implicated.These effector CD8+ T cells can release perforin, thereby directly damaging tissue. 11In a case report by Pilz et al., a patient with recurrent TDLs who was treated with fingolimod had a higher concentration of CD8+ T cell in the CSF than in the peripheral blood. 13nother theory suggests that individuals with impaired adaptive cell immunity may have an overreaction of the innate immune system as a compensation mechanism.Cytokine effects rather than direct T-or B-cell immunotoxicity may underlie the vasogenic edema and macrophage activation observed in TDLs, thus elucidating the occurrence of these lesions in lymphopenic patients. 11,14CS represents a severe monophasic demyelinating disorder, classified as a rare subtype of MS. 15 Patients typically present with focal neurological deficits, headache, dizziness, poor cognition, and convulsions. 16BCS is characterized by a lesion with demyelination rings mixing with undamaged myelin rings. 17Lesions have been reported in the brain stem, spinal cord, cerebellum, hemispheres, and optic chiasm. 18Treatment approaches for BCS are still controversial; however, there are several treatment options for BCS.Corticosteroids are primarily used for acute BCS lesions, while Interferon beta-1a, mitoxantrone, natalizumab, and rituximab are utilized for maintenance treatment. 19Rituximab has been considered effective for patients who had BCS with typical MS lesions and responded poorly to steroids, indicating it could be a suitable treatment option in these cases.However, it highlights the need for personalized treatment approaches based on individual patient characteristics and response to initial therapies. 61][22] As mentioned earlier, TDLs constitute a range of demyelinating illnesses, of which BCS is considered a rare subvariant of TDLs. 23However, TDLs and BCS can differ in appearance, etiology, and relationship to MS. TDLs are characterized by their large size (usually >2 cm) and atypical features, including edema, open ring enhancement on MRI, and mass effect.On the other hand, BCS is characterized by its specific pattern of demyelination on T2-weighted MRI sequences, radiologically as two or more concentric rings of alternating hyperintensity and hypointensity. 24From an etiological perspective and their relationship to MS, BCS is seen as a distinct disorder or a variety of MS, but TDLs can develop in people with different demyelinating diseases, which does not necessarily include MS. 5,12,15 The case described herein involves a known MS patient who had been undergoing fingolimod therapy for 3 years preceding the identification of a Balo-like lesion on MRI.A comprehensive diagnostic evaluation excluded alternative diagnoses mimicking Balo-like lesions, including intracranial neoplasms and infectious etiologies.There is a growing body of literature suggesting a possible association between fingolimod therapy and the development of new TDLs in MS patients, 7,13,25 In a study by Baghbanian et al., a 32-year-old MS patient receiving fingolimod treatment who acquired Balo-like lesions was described.She had symptoms such as fatigue, uncontrolled crying, and paralysis of the left side, but testing revealed no indication of cancer or metastases.The patient responded dramatically to corticosteroid pulse therapy. 7Nevertheless, reports of Balo-like lesion development in MS patients receiving fingolimod remain largely anecdotal.Furthermore, while BCS is usually considered to be a precursor to MS, the occurrence of new BCS lesions in MS patients undergoing fingolimod therapy is unusual. 26It is unclear whether the development of a Balo-like lesion in this case is associated with a new MS attack or the use of fingolimod.However, the possibility of an association between new BCS and fingolimod use needs further investigation.

F I G U R E 1
(A) Brain MRI T1weighted image showed multiple hypointense lesions.(B, C) T2-and flair revealed multiple hyperintense lesions.One of them located in left centrum semiovale had multiple hypo-and hyperintense layers, (D) with closed ring enhancement.MRI, magnetic resonance imaging.